Hemophilia A is one of the most common forms of the inherited bleeding disorder of hemophilia. It is caused by a deficiency of the blood-clotting protein called factor VIII. Without enough of this protein, the blood cannot clot properly, which makes internal bleeding into joints or organs after injuries or even without obvious triggers a severe and sometimes life-threatening risk. To prevent these complications, people with hemophilia rely on regular treatments that replace their missing clotting factors.
Despite decades of research, long-standing mysteries have surrounded which specific cells in the body produce factor VIII in healthy individuals. Now, new research from scientists at the Indiana University School of Medicine’s Herman B Wells Center for Pediatric Research is clarifying misconceptions and providing a clearer look into more effective gene therapies for the disease.
In a study recently published in Blood Advances, researchers sought to “map” where factor VIII is made in the body. Using mouse models and human tissue samples, they discovered that within the liver, the protein is primarily produced in a subset of specialized cells lining small blood vessels. These liver sinusoidal endothelial cells (LSECs) sit in a specific region in the liver surrounding the central veins, which collect blood on its way back from the liver to the general circulation. Outside the liver, they discovered that only the kidney’s endothelial cells produce a meaningful amount of factor VIII.
“Verifying that factor VIII production is concentrated in very specific anatomical regions of the liver's microscopic structure is an exciting discovery,” said Radek Kaczmarek, PhD, assistant research professor of pediatrics at the IU School of Medicine and co-senior author of the study. “We were also surprised to find how consistent this pattern is. The same ‘zonal’ production occurs in both mice and humans, and it remains remarkably stable even in the presence of liver diseases like fatty liver disease.”
The researchers also confirmed that liver cells known as hepatocytes, which were long thought to be the source of factor VIII because other clotting factors are produced there, were not a contributing source. This finding is especially relevant for hemophilia A gene therapies, as current treatments target hepatocytes.
“This mismatch may explain why the current gene therapy loses efficacy over time or causes side effects like liver inflammation,” Kaczmarek said. “Identifying the LSECs as the natural main producers makes the case for development of precision gene therapies that would target these specific cells. Making the protein in its natural environment could make the treatment more effective and safer.”
Kaczmarek said the study’s findings prove that “all endothelial cells are not created equal, not even in the same organ.” He hopes their discoveries will help optimize gene delivery systems to avoid problems common with current factor VIII therapies and provide people with hemophilia A safer and more effective options.
“People with hemophilia A still await durable and reliable gene therapy,” he said.
IU School of Medicine’s Paige E. Severeid, Wenjun Zhang, Chandrashekhar A. Kubal, Renzhi Han, Sreevani Arisa and Roland W. Herzog are co-authors on the study. Additional authors include Audrey Kapelanski-Lamoureux, Peter Metrakos and Anthoula Lazaris at McGill University; Cynthia Lebeaupin and Randal J. Kaufman at Sanford Burnham Prebys Medical Discovery Institute; Oded Danziger and Brad R. Rosenberg at Icahn School of Medicine; and Eleftherios Michailidis, Charles M. Rice and Ype P. de Jong at The Rockefeller University.
This research was supported by funding from the National Institutes of Health, the Indiana Collaborative Initiative for Talent Enrichment (provided by Lilly Endowment) and the Riley Children's Foundation.
